Combination of a nicotinic receptor partial agonist and of an acetylcholinesterase inhibitor, pharmaceutical composition containing same and use thereof in the treatment of cognitive disorders

Abstract

The combination of an alpha-7 nicotinic receptor agonist and of an acetylcholinesterase inhibitor, pharmaceutical composition comprising the combination and the use thereof in the treatment of cognitive disorders.

1 . A combination of an alpha-7 nicotinic receptor partial agonist and an acetylcholinesterase inhibitor. 
     
     
         2 . The combination according to  claim 1 , wherein the alpha-7 nicotinic receptor partial agonist is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X represents an oxygen atom or a group of formula NZ in which Z represents a hydrogen atom or a (C 1 -C 6 )alkyl group, 
 n represents the number 0, 1 or 2, and 
 R 1 , R 2 , R 3 , R 4  and R 5  each represent, independently of one another, a hydrogen or halogen atom, or a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a hydroxyl group, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkoxy group, a phenoxy group or a phenyl group which is optionally substituted with a halogen atom or a trifluoromethyl group, a cyano group, a hydroxyl group, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group, or else R 2  and R 3  together form a group of formula —OCH 2 O— or —CH 2 CH 2 CH 2 CH 2 —, 
 or an acid addition salt, hydrate or solvate thereof. 
 
     
     
         3 . The combination according to  claim 2 , wherein:
 X represents an oxygen atom;   n represents the number 0;   R 1 , R 2 , R 4  and R 5  each represent a hydrogen atom; and   R 3  represents a halogen atom;   or an acid addition salt, hydrate or solvate thereof.   
     
     
         4 . The combination according to  claim 2 , wherein the alpha-7 nicotinic receptor partial agonist is 4-bromophenyl 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate, or an acid addition salt, hydrate or solvate thereof. 
     
     
         5 . The combination according to  claim 4 , wherein the 4-bromophenyl 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate is in the form of the (2E)-but-2-enedioate salt. 
     
     
         6 . The combination according to  claim 1 , wherein the acetylcholinesterase inhibitor is chosen from rivastigmine and donepezil. 
     
     
         7 . The combination according to  claim 2 , wherein the acetylcholinesterase inhibitor is chosen from rivastigmine and donepezil. 
     
     
         8 . The combination according to  claim 3 , wherein the acetylcholinesterase inhibitor is chosen from rivastigmine and donepezil. 
     
     
         9 . The combination according to  claim 1 , wherein the alpha-7 nicotinic receptor partial agonist is 4-bromophenyl 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate (2E)-but-2-enedioate and the acetylcholinesterase inhibitor is rivastigmine. 
     
     
         10 . The combination according to  claim 1 , wherein the alpha-7 nicotinic receptor partial agonist is 4-bromophenyl 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate (2E)-but-2-enedioate and the acetylcholinesterase inhibitor is donepezil. 
     
     
         11 . A pharmaceutical composition comprising the combination according to  claim 1 , and at least one pharmaceutically acceptable excipient. 
     
     
         12 . A pharmaceutical composition comprising the combination according to  claim 2 , and at least one pharmaceutically acceptable excipient. 
     
     
         13 . A pharmaceutical composition comprising the combination according to  claim 3 , and at least one pharmaceutically acceptable excipient. 
     
     
         14 . A pharmaceutical composition comprising the combination according to  claim 9 , and at least one pharmaceutically acceptable excipient. 
     
     
         15 . A pharmaceutical composition comprising the combination according to  claim 10 , and at least one pharmaceutically acceptable excipient. 
     
     
         16 . A kit comprising an alpha-7 nicotinic receptor partial agonist and an acetylcholinesterase inhibitor, wherein the alpha-7 nicotinic receptor partial agonist and the acetylcholinesterase inhibitor are in separate compartments and being intended to be administered simultaneously, separately or spread out over time (sequential administration). 
     
     
         17 . The kit according to  claim 16 , wherein the alpha-7 nicotinic receptor partial agonist is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X represents an oxygen atom or a group of formula NZ in which Z represents a hydrogen atom or a (C 1 -C 6 )alkyl group, 
 n represents the number 0, 1 or 2, and 
 R 1 , R 2 , R 3 , R 4  and R 5  each represent, independently of one another, a hydrogen or halogen atom, or a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a hydroxyl group, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkoxy group, a phenoxy group or a phenyl group which is optionally substituted with a halogen atom or a trifluoromethyl group, a cyano group, a hydroxyl group, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group, or else R 2  and R 3  together form a group of formula —OCH 2 O— or —CH 2 CH 2 CH 2 CH 2 —, 
 or an acid addition salt, hydrate or solvate thereof. 
 
     
     
         18 . The kit according to  claim 16 , wherein the alpha-7 nicotinic receptor partial agonist is 4-bromophenyl 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate, or an acid addition salt, hydrate or solvate thereof. 
     
     
         19 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 1 . 
     
     
         20 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 2 . 
     
     
         21 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 3 . 
     
     
         22 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 4 . 
     
     
         23 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 5 . 
     
     
         24 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 6 . 
     
     
         25 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 7 . 
     
     
         26 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 8 . 
     
     
         27 . A method of treating a cognitive disorder in a patient, comprising administering to said patient the combination according to  claim 9 . 
     
     
         28 . The method according to  claim 19 , wherein the cognitive disorder is related to Alzheimer's disease.